The NF-kappaB transcription factor family and the family of IkappaB proteins which regulate the function of these transcription factors are both critical for the defense of the organism since they control the expression of many immunomodulatory proteins as well as proteins which counteract stress. In addition, these proteins regulate the expression of HIV. The overall NF-kappaB and IkappaB activity in a given cell constitutes itself out of the functions of the individual family members which are expressed in that cell. An understanding of the unique functions of the various family members may offer highly specific and limited targets for immunomodulatory therapies. We have initiated a study to dissect the roles of specific individual members of these two families by generating so-called "knock-out" mice which lack expression of either p52, a subunit of NF-kappaB, or Bcl-3, an IkappaB family member whose physiologic role is largely unknown. These mice will be challenged with viruses and pathogens to uncover specific roles of these proteins during immune responses. We are also generating transgenic mice which overexpress these and other family members. Since the p52 and Bcl-3 gene have been found as partners in recurrent chromosomal translocations in certain B- and T cell tumors, our studies will be essential to understand the role these proteins can play during tumorigenesis. Individual functions of the NF-kappaB complexes are also being investigated in the context of a given promoter. We discovered that some of the NF-kappaB transcription factors may exert their influence well beyond those genes which harbor known kappaB binding sites in their regulatory regions; the NF-kappaB subunits p65 and c-Rel can interact with the serum response factor and thereby strongly and positively affect transcriptional activation through the SRE, the SRF binding element present in the regulatory regions of many signal-inducible genes. Finally, studies aimed at understanding the role of NF-kappaB during cellular infection with HIV uncovered a correlation between low infectivity and the presence of seprocidin proteases in monocyte/macrophages.